{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T11:59:16Z","timestamp":1790251156474,"version":"4.1.0"},"reference-count":31,"publisher":"National Academy of Sciences","issue":"20","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2013,5,14]]},"abstract":"<jats:p>\n                    Genome-wide association studies (GWAS) are a powerful means of identifying genes with disease-associated common variants, but they are not well-suited to detecting genes with disease-associated rare and low-frequency variants. In the current study of Beh\u00e7et disease (BD), nonsynonymous variants (NSVs) identified by deep exonic resequencing of 10 genes found by GWAS (\n                    <jats:italic>IL10, IL23R<\/jats:italic>\n                    ,\n                    <jats:italic>CCR1<\/jats:italic>\n                    ,\n                    <jats:italic>STAT4<\/jats:italic>\n                    ,\n                    <jats:italic>KLRK1<\/jats:italic>\n                    ,\n                    <jats:italic>KLRC1, KLRC2, KLRC3, KLRC4<\/jats:italic>\n                    , and\n                    <jats:italic>ERAP1<\/jats:italic>\n                    ) and 11 genes selected for their role in innate immunity\n                    <jats:italic>(IL1B, IL1R1, IL1RN, NLRP3, MEFV, TNFRSF1A, PSTPIP1, CASP1, PYCARD, NOD2, and TLR4<\/jats:italic>\n                    ) were evaluated for BD association. A differential distribution of the rare and low-frequency NSVs of a gene in 2,461 BD cases compared with 2,458 controls indicated their collective association with disease. By stringent criteria requiring at least a single burden test with study-wide significance and a corroborating test with at least nominal significance, rare and low-frequency NSVs in one GWAS-identified gene,\n                    <jats:italic>IL23R<\/jats:italic>\n                    (\n                    <jats:italic>P<\/jats:italic>\n                    = 6.9 \u00d7 10\n                    <jats:sup>\u22125<\/jats:sup>\n                    ), and one gene involved in innate immunity,\n                    <jats:italic>TLR4<\/jats:italic>\n                    (\n                    <jats:italic>P<\/jats:italic>\n                    = 8.0 \u00d7 10\n                    <jats:sup>\u22124<\/jats:sup>\n                    ), were associated with BD. In addition, damaging or rare damaging\n                    <jats:italic>NOD2<\/jats:italic>\n                    variants were nominally significant across all three burden tests applied (\n                    <jats:italic>P<\/jats:italic>\n                    = 0.0063\u20130.045). Furthermore, carriage of the familial Mediterranean fever gene (\n                    <jats:italic>MEFV<\/jats:italic>\n                    ) mutation Met694Val, which is known to cause recessively inherited familial Mediterranean fever, conferred BD risk in the Turkish population (OR, 2.65;\n                    <jats:italic>P<\/jats:italic>\n                    = 1.8 \u00d7 10\n                    <jats:sup>\u221212<\/jats:sup>\n                    ). The disease-associated NSVs in\n                    <jats:italic>MEFV<\/jats:italic>\n                    and\n                    <jats:italic>TLR4<\/jats:italic>\n                    implicate innate immune and bacterial sensing mechanisms in BD pathogenesis.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1306352110","type":"journal-article","created":{"date-parts":[[2013,5,1]],"date-time":"2013-05-01T08:22:51Z","timestamp":1367396571000},"page":"8134-8139","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":153,"title":["Targeted resequencing implicates the familial Mediterranean fever gene\n                    <i>MEFV<\/i>\n                    and the toll-like receptor 4 gene\n                    <i>TLR4<\/i>\n                    in Beh\u00e7et disease"],"prefix":"10.1073","volume":"110","author":[{"given":"Yohei","family":"Kirino","sequence":"first","affiliation":[{"name":"Inflammatory Disease Section, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-1849;"},{"name":"Departments of bInternal Medicine and Clinical Immunology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Zhou","sequence":"additional","affiliation":[{"name":"Inflammatory Disease Section, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-1849;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshiaki","family":"Ishigatsubo","sequence":"additional","affiliation":[{"name":"Departments of bInternal Medicine and Clinical Immunology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobuhisa","family":"Mizuki","sequence":"additional","affiliation":[{"name":"Ophthalmology and Visual Science, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilknur","family":"Tugal-Tutkun","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Istanbul Faculty of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emire","family":"Seyahi","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Internal Medicine and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yilmaz","family":"\u00d6zyazgan","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Cerrahpa\u015fa Faculty of Medicine, Istanbul University, Istanbul 34098, Turkey;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serdal","family":"Ugurlu","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Internal Medicine and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Burak","family":"Erer","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul 34093, Turkey;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neslihan","family":"Abaci","sequence":"additional","affiliation":[{"name":"Department of Genetics, Institute for Experimental Medicine, Istanbul University, Istanbul 34093, Turkey;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Duran","family":"Ustek","sequence":"additional","affiliation":[{"name":"Department of Genetics, Institute for Experimental Medicine, Istanbul University, Istanbul 34093, Turkey;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akira","family":"Meguro","sequence":"additional","affiliation":[{"name":"Ophthalmology and Visual Science, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsuhisa","family":"Ueda","sequence":"additional","affiliation":[{"name":"Departments of bInternal Medicine and Clinical Immunology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitsuhiro","family":"Takeno","sequence":"additional","affiliation":[{"name":"Departments of bInternal Medicine and Clinical Immunology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hidetoshi","family":"Inoko","sequence":"additional","affiliation":[{"name":"Division of Molecular Medical Science and Molecular Medicine, Department of Molecular Life Science, Tokai University School of Medicine, Isehara 259-1193, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Ombrello","sequence":"additional","affiliation":[{"name":"Inflammatory Disease Section, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-1849;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colleen L.","family":"Satorius","sequence":"additional","affiliation":[{"name":"Inflammatory Disease Section, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-1849;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baishali","family":"Maskeri","sequence":"additional","affiliation":[{"name":"NIH Intramural Sequencing Center, National Human Genome Research Institute, National Institutes of Health, Rockville, MD 20852;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James C.","family":"Mullikin","sequence":"additional","affiliation":[{"name":"NIH Intramural Sequencing Center, National Human Genome Research Institute, National Institutes of Health, Rockville, MD 20852;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong-Wei","family":"Sun","sequence":"additional","affiliation":[{"name":"Biodata Mining and Discovery Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892-1560;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gustavo","family":"Gutierrez-Cruz","sequence":"additional","affiliation":[{"name":"Genome Analysis Core Facility, Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892-8024; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoonhee","family":"Kim","sequence":"additional","affiliation":[{"name":"Genometrics Section, Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, MD 21224"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander F.","family":"Wilson","sequence":"additional","affiliation":[{"name":"Genometrics Section, Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, MD 21224"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel L.","family":"Kastner","sequence":"additional","affiliation":[{"name":"Inflammatory Disease Section, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-1849;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmet","family":"G\u00fcl","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul 34093, Turkey;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elaine 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